Sepsis is a clinical syndrome that results from an activated systemic host inflammatory response to infection. In its more severe form, sepsis affects almost 800,000 North Americans each year, and results in the deaths of approximately 30% of these. It is the leading cause of morbidity for patients admitted to a contemporary intensive care unit (ICU), through the development of a syndrome of disseminated organ injury, known as the multiple organ dysfunction syndrome. Sepsis is characterized by an overwhelming systemic response to infection and may lead to septic shock. Septic shock is a life threatening immunological reaction to a severe infection. Septic shock is caused by the presence of large numbers of bacteria in the blood stream; symptoms include a fall in blood pressure, impaired ability of the blood to clot and damage to major organs including kidneys, liver and lungs.
Septic shock is becoming increasingly common in the North American population because of an increasing population at risk: a larger proportion of elderly individuals including many with chronic debilitating disease, and increasing numbers of people with impaired immunity due to disease such as cancer and AIDS. About 400,000 cases of sepsis, 200,000 cases of septic shock and 100,000 deaths from both occur each year in the U.S.
Researchers continue to experiment with medication to fight the infection and control the inflammatory response associated with sepsis and septic shock. However, the 50% mortality rate associated with septic shock has improved little in the last 30 years despite innovations in antibiotic therapy and life support modalities. To combat the condition, hospitals currently administer drugs and fluids to patients maintain blood pressure and use antibiotics to fight the infection.
Epidemiologic surveys have demonstrated that tissue injury secondary to activation of the inflammatory system may also complicate noninfectious disorders (e.g. acute pancreatitis and ischemia-reperfusion). The term systemic inflammatory response syndrome (SIRS) is used in this setting to refer to the consequences of a dysregulated host inflammatory response when infection is not present. SIRS is a widespread inflammatory response to a variety of severe clinical results.
It is important to distinguish between an underlying disease (infection or pancreatitis) and the host's response (sepsis or SIRS). This distinction is important clinically since it is the latter, not the primary disease, that is responsible for the multiple organ dysfunction syndrome (MODS). MODS is the usual explanation for the high mortality rates associated with these syndromes.
Several investigators have shown that a depression in cardiac contractility is an important component of hemodynamic collapse in sepsis (1,2). Some have attributed this cardiac dysfunction to a low molecular weight substance that is present in septic plasma (3-4). Lefer and coworkers suggested, on the basis of a large body of work, primarily in animal models of hemorrhagic shock, that myocardial depressant factor was a small molecular weight peptide originating from the pancreas (3,4). Others suggested that this substance was a cytokine released into the circulation as part of the inflammatory reaction induced by the infecting organism (5). However, there is no clear consensus about the origin or biochemical nature of myocardial depressant substance(s) in sepsis. Indeed, the very existence of such a factor has remained controversial.
The inventors previously provided additional evidence for the existence of a myocardial depressant factor in sepsis (6). In an Escherichia coli model of induced sepsis in dogs, Gomez et al (6) showed that myocardial depression developed after 4 h of bacteremia and that this depression could be reversed by removal of a circulating substance of <30,000 molecular weight from the plasma by continuous arteriovenous hemofiltration. Myocardial depressant activity in plasma [filterable cardiodepressant substance (FCS)] was detected by a bioassay that included a right ventricular trabecular preparation. FCS activity was detected in the plasma as early as 1 h after sepsis and increased further at the 4 h interval. Hemofiltration returned FCS activity to preseptic levels.
In a subsequent study, the inventors further characterized the nature of FCS (7). By pore filtration techniques, the inventors found that FCS was contained in the 10-30 kilodalton (KD) fraction of plasma, was found in the acetone-insoluble portion of plasma, and that its activity could be diminished by the proteolytic enzyme proteinase-K. This suggested that FCS was likely to be a protein.